MON-366 Lonigutamab, a Novel Anti-IGF-1R, Has a Limited Impact on Circulating IGF-1 Levels

Abstract Disclosure: G.J. Kahaly: ACELYRIN, INC., Amgen Inc, Immunovant, QuidelOrtho, Sling, Viridian Therapeutics. P.S. Subramanian: ACELYRIN, INC., American Academy of Ophthalmology, Amgen Inc, Argenx, Genentech, Inc., GenSight Biologics, Immunovant, Kriya Therapeutics, North American Neuro-Ophthalmology Society, Santhera Pharmaceuticals, Tourmaline Bio, Viridian Therapeutics, Wolters Kluwer. A. Nyborg: ACELYRIN, INC. A. Nguyen: ACELYRIN, INC. A. Grover: ACELYRIN, INC. P.R. de Jong: ACELYRIN, INC. B. Welch: ACELYRIN, INC. C. Archer: ACELYRIN, INC. S. Imm: ACELYRIN, INC. S. Mpofu: ACELYRIN, INC. S. Ugradar: ACELYRIN, INC., Viridian Therapeutics. Background: Insulin-like growth factor 1 receptor (IGF-1R) pathway inhibition has shown clinical benefit in patients with thyroid eye disease (TED). However, anti-IGF-1R monoclonal antibodies (mAbs) that directly compete with IGF-1 for receptor binding reportedly increase serum IGF-1 levels by 250%-700% (1,2). As IGF-1 has pleiotropic effects on numerous body systems, elevated IGF-1 levels may contribute to the adverse event profile associated with competitive anti-IGF-1Rs, such as hyperglycemic events and menstrual disorders (3,4). Thus, limiting the increase in IGF-1 levels may help to reduce side effects of treatment. Lonigutamab is a novel, non-competitive, high-affinity, subcutaneously (SC) administered (5), anti-IGF-1R mAb being evaluated for the treatment of TED. Objective: This study tests the hypothesis that lonigutamab has a limited impact on circulating IGF-1 at target-saturating levels (5) relative to the increases in IGF-1 levels reported with competitive IGF-1R inhibitors. Methods: We conducted phase 1 trials in healthy volunteers (HVs), including a single ascending dose (SAD) study with intravenous (0.1-3.0 mg/kg) and SC dosing (20-250 mg) and a multiple dose (MD) study (SC: 75 mg loading dose on day 1; 37.5 mg on days 8/15). IGF-1 levels were measured by ELISA (R&D Systems Quantikine immunoassay) pre-dose, daily, and at regular intervals thereafter. Results: In total, the studies included 53 HVs. In the SAD study, lonigutamab demonstrated modest increases in IGF-1 levels (peaking on days 4-8 at ∼20%-80% from baseline across cohorts) when maintained above target saturation (doses hypothesized to be therapeutic). IGF-1 levels returned to baseline between days 10 and 57, corresponding to a decrease in target saturation and pharmacokinetics. The MD study showed a similar pattern of modest, transient IGF-1 elevation (∼30%-80%). Conclusions: Overall, lonigutamab exhibited limited elevation of serum IGF-1 levels in HVs relative to previously published increases in IGF-1 levels reported with competitive IGF-1R inhibitors. These findings support lonigutamab’s unique non-competitive mechanism of action, which may translate to an improved safety profile while maintaining the therapeutic benefit of IGF-1R pathway inhibition, and warrant further investigation of lonigutamab as a therapeutic option in TED. References: 1. Kurzrock R, et al. Clin Cancer Res. 2010;16:2458-2465. 2. Foster K, et al. Poster at ATA Annual Meeting 2023. #213. 3. Wang X, et al. Endocrine. 2024;85:313-320. 4. Terrarosa A, et al. Ophthalmic Plast Reconstr Surg. 2024;40:312-315. 5. Keenan G, et al. Poster at NANOS Annual Meeting 2023. #293. Presentation: Monday, July 14, 2025